1hbj



X-ray crystal structure of complex between T. californica AChE and a reversible inhibitor, 4-amino-5-fluoro-2-methyl-3-(3-trifluroactylbenzylthiomethyl) quinoline

Overview
Chimeras of tacrine and m-(N,N,N-Trimethylammonio)trifluoroacetophenone, (1) were designed as novel, reversible inhibitors of acetylcholinesterase., On the basis of the X-ray structure of the apoenzyme, a molecular modeling, study determined the favored attachment positions on the 4-aminoquinoline, ring (position 3 and the 4-amino nitrogen) and the favored lengths of a, polymethylene link between the two moieties (respectively 5-6 and 4-5, sp(3) atoms). Seven compounds matching these criteria were synthesized, and their inhibitory potencies were determined to be in the low nanomolar, range. Activity data for close analogues lacking some of the postulated, key features showed that our predictions were correct. In addition, a, subsequent crystal structure of acetylcholinesterase complexed with the, most active compound 27 was in good agreement with our model. The design, strategy is therefore validated and can now be developed further.

About this Structure
1HBJ is a Single protein structure of sequence from Torpedo californica with NAG, FBQ, MES and PG4 as ligands. Active as Acetylcholinesterase, with EC number 3.1.1.7 Known structural/functional Site: FBQ. Full crystallographic information is available from OCA.

Reference
A structure-based design approach to the development of novel, reversible AChE inhibitors., Doucet-Personeni C, Bentley PD, Fletcher RJ, Kinkaid A, Kryger G, Pirard B, Taylor A, Taylor R, Taylor J, Viner R, Silman I, Sussman JL, Greenblatt HM, Lewis T, J Med Chem. 2001 Sep 27;44(20):3203-15. PMID:11563919

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